Understanding the impact of known and new genetic factors in the context of novel therapies is paramount to best define the optimal treatment strategy for multiple myeloma (MM) patients. Our group has been at the forefront of prognosis determination based on genetic factors. In addition, we recently discovered that up to 50% of MM cases have constitutive activation of the NF-kB pathway, through multiple genetic mutations, all leading to increased activity of the non-canonical pathway. Importantly we have shown these patients have greatly increased sensitivity to bortezomib. The treatment of MM can no longer be conducted under a one size fits all approach, and it is imperative that we validate genetic prognostic and predictive markers for the selection of MM treatments. While novel therapeutic agents have improved the overall prospects for patients, the net effect might be different based on the molecular subtypes. Some of the novel therapies and strategies have the potential to improve the outcome of high risk-MM (HR-MM). Patients with standard risk MM (SR- MM) might benefit from simpler, less toxic, interventions, while HR-MM patients will need the introduction of more intensive regimens such as early bortezomib and/or non-myeloablative allogeneic stem cell transplant (NM-SCT) strategies. To address these issues, and at center of this project proposal, we ask the following questions: 1. Can thalidomide and lenalidomide overcome the negative prognosis of HR-MM? 2. Can we identify new genomic markers associated with long time to progression in patients treated with lenalidomide and thalidomide? 3. Can bortezomib result in better responses and outcome in patients with HR-MM? 4. Can NF-kB hyperactivation or TRAF3 inactivation predict improved outcome with bortezomib? 5. Can NM-SCT overcome the poor prognosis of t(4;14)(p16;q32)? To address these questions we propose the following experiments, using a panel of molecular and genetic assays employing clinical samples associated with five Phase 3 clinical trials. Globally these trials include over 1500 patient treated with various combinations of lenalidomide, thalidomide and bortezomib. They include the ECOG clinical trials E1A00, E4A03, E1A05 and E1A06. In addition we propose to study the prognostic significance of t(4;14)(p16;q32) in a large randomized trial (n = 700) addressing the role of NM-SCT for newly diagnosed MM. To do so we will examine research samples associated with the clinical trial BMT CTN 0102.